Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations have been performed to investigate the influence of Se and Te substitutions on the stability of tetrahedrite. The formation energies, the Laplacian of the electron density, the total and local volume changes and the site charge changes have been determined. The DFT results show that the single-atom substitution is the most preferred, and that selenium is preferred for sulphur replacement, whereas antimony can be equally replaced by selenium and tellurium. However, as selenium substitutes for either sulphur or antimony, QTAIM calculations evidenced large structural and chemical changes in the structures. Additional experimental results, in agreement with QTAIM results, allow us to conclude that the investigation of alloy stability cannot be limited to DFT calculations of formation energies and total volume changes. QTAIM appears to be a valuable complementary method for obtaining information on phase stability.